Mechanisms involved in corticotropin-releasing factor-induced excitation of entorhinal neurons and facilitation of glutamate release at the perforant pathway.

The entorhinal cortex (EC) is closely related to emotional control, consolidation and recall of memories, Alzheimer's disease, schizophrenia, and temporal lobe epilepsy. Corticotropin-releasing factor (CRF) is also implicated in these physiological functions and pathological disorders. Although both CRF peptide and CRF2 receptors are expressed in the EC, their roles and underlying cellular and molecular mechanisms in the EC have not been determined. Here, we found that activation of CRF2 receptors excited layer II principal neurons in the medial EC of rats and mice aged 18 to 28 days via elevation of intracellular cAMP level without the requirement of protein kinase A (PKA). Construction of the current-voltage (I-V) relationship of the CRF-induced currents suggested that CRF-induced excitation of layer II entorhinal neurons was mediated by activation of HCN channels and depression of inwardly rectifying K+ (Kir) channels. With perforated-patch recording, we further found that CRF upregulated Ih currents recorded from layer II EC neurons by elevation of intracellular cAMP. Activation of CRF2 receptors further enhanced glutamate release at the perforant path (PP)-dentate gyrus (DG) granule cell (GC) synapses via enlarging the size of the readily releasable pool. HCN channels and elevation of presynaptic Ca2+ were involved in CRF-mediated augmentation of glutamate release at the PP-GC synapses. Our results may provide a cellular and molecular mechanism to explain the functions of CRF in vivo.NEW & NOTEWORTHY Corticotropin-releasing factor (CRF) excites entorhinal neurons and facilitates glutamate release at the perforant path (PP)-granule cell (GC) synapses by activating CRF2 receptors. CRF2-mediated elevation of cAMP activates HCN channels and depresses Kir channels to depolarize entorhinal cortex neurons. CRF-mediated depolarization leads to an increase in intracellular calcium resulting in augmentation of the readily releasable pool size to facilitate glutamate release at the PP-GC synapses.